A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury

Delbary-Gossart, Sandrine; Lee, Sangmi; Baroni, Marco Giorgio; Lamarche, Isabelle; Arnone, M.; Canolle, Benoit; Lin, Amity; Sacramento, Jeffrey; Salegio, Ernesto A.; Castel, Marie-Noëlle; Delesque-Touchard, Nathalie; Alam, Antoine; Laboudie, Patricia; Ferzaz, Badia; Savi, Pierre; Herbert, Jean‐Marc; Manley, Geoffrey T.; Ferguson, Adam R.; Bresnahan, Jacqueline C.; Bono, Françoise; Beattie, Michael S.

doi:10.1093/brain/aww074

Cited by 46 publications

(33 citation statements)

References 45 publications

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“…However, this study only tested the effects of the p75 NTR antagonist on other members of the TNF receptor family with cysteine‐rich domains. Thus, they did not exclude interactions of this antagonist with other extracellular receptors which may be an explanation for the altered cell recruitment and activation (Delbary‐Gossart et al, ).…”

Section: Discussionmentioning

confidence: 99%

p75^NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

Düsedau

Alexander

Figueiredo

et al. 2018

Glia

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Neurotrophins mediate neuronal growth, differentiation, and survival via tropomyosin receptor kinase (Trk) or p75 neurotrophin receptor (p75 NTR ) signaling. The p75 NTR is not exclusively expressed by neurons but also by certain immune cells, implying a role for neurotrophin signaling in the immune system. In this study, we investigated the effect of p75 NTR on innate immune cell behavior and on neuronal morphology upon chronic Toxoplasma gondii ( T. gondii ) infection‐induced neuroinflammation. Characterization of the immune cells in the periphery and central nervous system (CNS) revealed that innate immune cell subsets in the brain upregulated p75 NTR upon infection in wild‐type mice. Although cell recruitment and phagocytic capacity of p75 NTRexonIV knockout (p75 −/− ) mice were not impaired, the activation status of resident microglia and recruited myeloid cell subsets was altered. Importantly, recruited mononuclear cells in brains of infected p75 −/− mice upregulated the production of the cytokines interleukin (IL)‐10, IL‐6 as well as IL‐1α. Protein levels of proBDNF, known to negatively influence neuronal morphology by binding p75 NTR , were highly increased upon chronic infection in the brain of wild‐type and p75 −/− mice. Moreover, upon infection the activated immune cells contributed to the proBDNF release. Notably, the neuroinflammation‐induced changes in spine density were rescued in the p75 −/− mice. In conclusion, these findings indicate that neurotrophin signaling via the p75 NTR affects innate immune cell behavior, thus, influencing the structural plasticity of neurons under inflammatory conditions.

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Section: Discussionmentioning

confidence: 99%

p75^NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

Düsedau

Alexander

Figueiredo

et al. 2018

Glia

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“…There have been many reports concerning the physiological and pathological changes after brain injury (Kraus et al, 2007; Roth et al, 2014; Kondo et al, 2015; Delbary-Gossart et al, 2016), and the proliferation and migration of autologous NSCs is a focus of study (Hu et al, 2014; Wang et al, 2016). It has been reported that modeling strokes and TBI in animals has allowed the identification of a unique response in the sub ventricular zone (SVZ), where endogenous neural stem/progenitor cells (NSPCs) undergo transient expansion and begin to migrate to sites of tissue damage (Chen et al, 2003; Thored et al, 2006, 2007).…”

Section: Discussionmentioning

confidence: 99%

The Expression of NP847 and Sox2 after TBI and Its Influence on NSCs

Bao

Chen

et al. 2016

Front. Cell. Neurosci.

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The proliferation and differentiation of neural stem cells (NSCs) is important for neural regeneration after cerebral injury. Here, for the first time, we show that phosphorylated (p)-ser847-nNOS (NP847), rather than nNOS, may play a major role in NSC proliferation after traumatic brain injury (TBI). Western blot results demonstrated that the expression of NP847 and Sox2 in the hippocampus is up-regulated after TBI, and they both peak 3 days after brain injury. In addition, an immunofluorescence experiment indicated that NP847 and Sox2 partly co-localize in the nuclei of NSCs after TBI. Further immunoprecipitation experiments found that NP847 and Sox2 can directly interact with each other in NSCs. Moreover, in an OGD model of NSCs, NP847 expression is decreased, which is followed by the down-regulation of Sox2. Interestingly, in this study, we did not observe changes in the expression of nNOS in the OGD model. Further research data suggest that the NP847-Sox2 complex may play a major role in NSCs through the Shh/Gli signaling pathway in a CaMKII-dependent manner after brain injury.

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“…p75 antagonist that is, EVT 901 was administered daily at an oral dose of 1 mg/kg for a period of 7 days (Delbary‐Gossart et al . ). A corresponding volume of vehicle was administered orally to the placebo animals respectively.…”

Section: Methodsmentioning

confidence: 97%

“…Vitamin E a potent antioxidant was administered daily at an oral dose of 100 mg/kg body weight for the stipulated duration of drug administration (Hong et al 2004). p75 antagonist that is, EVT 901 was administered daily at an oral dose of 1 mg/kg for a period of 7 days (Delbary-Gossart et al 2016). A corresponding volume of vehicle was administered orally to the placebo animals respectively.…”

Section: Animalsmentioning

confidence: 99%

Hypoxia‐mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus

Sharma

Barhwal

Biswal

et al. 2018

Journal of Neurochemistry

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Brain‐derived neurotrophic factor (BDNF) which is primarily associated with neuronal survivability, differentiation and synaptic plasticity has been reported to mediate neurodegeneration in hypoxia through its p75 Neurotrophin receptors (p75NTR). The molecular events promoting BDNF‐mediated pro‐death signalling in hypoxia, however, still remain an enigma. This study attempts towards deciphering the signalling cascades involved in alteration of BDNF isoforms and its cognate receptor subtypes leading to neurodegeneration in hypoxia. Adult Sprague–Dawley rats were exposed to global hypobaric hypoxia simulating an altitude of 7620 m at standard temperature and humidity. Chronic hypoxic exposure for 7 days resulted in higher expression of pro‐BDNF and alteration in N‐linked glycosylation in hippocampus along with increased expression of endoplasmic reticulum stress markers viz., glucose‐regulated protein (Grp78), calnexin and changes in the endoplasmic reticulum morphology. Our findings reveal enriched expression of p75NTR in lipid rafts and higher expression of tyrosine receptor kinase β (Trkβ) in non‐raft regions following hypoxic exposure. Further investigations on membrane properties revealed decline in membrane fluidity along with increased cholesterol oxidation resulting in reduced translocation of Trkβ from non‐raft to raft regions. Supplementation of vitamin E during hypoxic exposure on the other hand reduced cholesterol oxidation and increased translocation of Trkβ from non‐raft to raft regions and promoted neuronal survival. Hence, our findings suggest a novel mechanism of cholesterol oxidation‐induced alteration in raft dynamics which is promotes p75 receptor‐mediated death signalling in hippocampal neurons during chronic hypoxia.

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A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury

Cited by 46 publications

References 45 publications

p75^NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

p75^NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

The Expression of NP847 and Sox2 after TBI and Its Influence on NSCs

Hypoxia‐mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus

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A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury

Cited by 46 publications

References 45 publications

p75NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

p75NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

The Expression of NP847 and Sox2 after TBI and Its Influence on NSCs

Hypoxia‐mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus

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Product

Resources

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p75^NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation

p75^NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection‐induced neuroinflammation